A variety of approaches have been developed to permit controlled, sustained release of a biologically active agent into a subject. Examples of controlled release systems include the polymeric compositions described in U.S. Pat. Nos. 4,938,763; 5,278,201 and 5,278,202. The compositions described in these patents are administered to the body of a subject in a flowable state. Once in the body, the composition coagulates or cures to form a solid implant.
One polymeric composition includes a thermoplastic polymer or copolymer, an organic solvent and a biologically active agent. The thermoplastic polymer is biocompatible, biodegradable and substantially insoluble in aqueous body or tissue fluids. The organic solvent is also biocompatible and miscible to dispersible in aqueous body or tissue fluids. The polymeric composition is flowable and can be introduced into the body using a syringe, for example. When the polymeric composition comes into contact with an aqueous medium. such as body or tissue fluid, the solvent dissipates or diffuses into the aqueous medium. Concurrently, the substantially insoluble thermoplastic polymer precipitates or coagulates to form a solid implant. As the thermoplastic polymer precipitates or coagulates to form the solid matrix, the active agent is trapped or encapsulated throughout the polymeric matrix. The biologically active agent is then released by dissolution or diffusion through the polymeric matrix and/or the biologically active agent is released as the matrix biodegrades.
However, the formation of the solid matrix from the flowable delivery system is not instantaneous. Typically the process can occur over a period of minutes to several hours. During this period, the rate of diffusion of the biologically active agent from the coagulating polymeric composition may be much more rapid than the rate of release that occurs from the subsequently formed solid matrix. This initial xe2x80x9cburstxe2x80x9d of biologically active agent that is released during implant formation may result in the loss or release of a large amount of the active agent. If the active agent is particularly toxic, this initial release or burst is likely to lead to toxic side effects and may damage adjacent tissues.
Therefore, a flowable delivery system that allows for the in situ formation of an implant while reducing or eliminating the initial xe2x80x9cburst effectxe2x80x9d would represent a significant advancement. Such delivery systems would permit higher concentrations of an active agent to be safely incorporated into an implant. The efficacy of such systems would also be improved, since a much greater percentage of the active agent would remain in the implant for sustained release and not be lost during the initial burst.
The invention is directed to a polymer composition which includes a base polymer that is a pharmaceutically acceptable, biocompatible, biodegradable and/or bioerodible, thermoplastic polymer or copolymer which is substantially insoluble in an aqueous medium; a pharmaceutically-acceptable, organic solvent that is miscible to dispersible in an aqueous medium; a biologically active agent; and a polymeric controlled release additive. Preferably, the controlled release additive is a poly(lactide-co-glycolide)/polyethylene glycol (PLG/PEG) block copolymer. When brought in contact with an aqueous enviroment, such as body or tissue fluids which typically surround tissues or organs in an organism, the organic solvent dissipates or disperses into the aqueous or body fluid. Concurrently, the substantially insoluble thermoplastic base polymer precipitates or coagulates to form a solid matrix or implant. The biologically active agent is trapped or encapsulated within the polymeric matrix as the implant solidifies. The polymeric controlled release additive reduces the initial burst of biologically active agent released from the polymeric composition as it is solidifying to form the solid implant. Once the solid implant is formed, the biologically active agent is released from the solid matrix by diffusion or dissolution from within the polymeric matrix and/or by the degradation of the polymeric matrix.
The invention is also directed towards methods of using the controlled release composition.
Definitions
As used herein, the term xe2x80x9ctissue sitexe2x80x9d includes any tissues in an organism. A tissue site is typically surrounded by an aqueous or body fluid such as interstitial fluid, blood, serum, cerebrospinal fluid or peritoneal fluid.
The term xe2x80x9ctissue defectxe2x80x9d is a subset of xe2x80x9ctissue sitexe2x80x9d and includes tissues, such as abraded tissue, traumatized tissue, a surgical incision or surgically resected tissue. Examples of tissue defects include, but are not limited to, surgical incisions in an internal organ such as an ovary, heart, liver, intestine, stomach, etc.
The term xe2x80x9cbiodegradablexe2x80x9d means that the polymer and/or polymer matrix of the film will degrade over time by the action of enzymes, by hydrolytic action and/or by other similar mechanisms in the human body. By xe2x80x9cbioerodible,xe2x80x9d it is meant that the film matrix will erode or degrade over time due, at least in part, to contact with substances found in the surrounding tissue fluids or cellular action. By xe2x80x9cbioabsorbable,xe2x80x9d it is meant that the polymer matrix will be broken down and absorbed within the human body, for example, by a cell or tissue. xe2x80x9cBiocompatiblexe2x80x9d means that neither the polymer, the solvent nor the resulting implant cause substantial tissue irritation or necrosis at the tissue site.
xe2x80x9cFlowablexe2x80x9d means that the polymer formulation is easy to manipulate and may be shaped and molded within the tissue site as it coagulates. Flowable includes formulations with a low viscosity or water-like consistency to those with a high viscosity, such as a paste-like material. Advantageously, the flowability of the polymer formulation allows it to conform to irregularities, crevices, cracks, and/or holes in the tissue site.
xe2x80x9cSubstantially insolublexe2x80x9d in an aqueous medium means that the thermoplastic polymer does not dissolve in an aqueous medium.
xe2x80x9cSolublexe2x80x9d in an organic solvent means that the thermoplastic polymer dissolves at a concentration of about 10% to about 70% by weight in an organic solvent.
xe2x80x9cInitial burstxe2x80x9d or xe2x80x9cBurst effectxe2x80x9d refers to the release of a biologically active agent from the polymeric composition during the first 24 hours after the polymeric composition is contacted with an aqueous fluid. The xe2x80x9cBurst effectxe2x80x9d is believed to be due to the increased release of biologically active agent from the polymeric composition while it is coagulating to form a solid implant and still in a flowable state.
The present invention relates to an in situ forming biodegradable implant useful as a delivery system for a biologically active agent to adjacent or distant tissues and organs in an animal. The polymer composition of the invention includes a base polymer that is a pharmaceutically acceptable, biocompatible, biodegradable and/or bioerodible, thermoplastic polymer or copolymer which is substantially insoluble in an aqueous medium; a pharmaceutically-acceptable, organic solvent that is miscible to dispersible in an aqueous medium; a polymeric controlled release additive; and a biologically active agent. Preferably, the controlled release additive is a poly(lactide-co-glycolide)/polyethylene glycol (PLG/PEG) block copolymer.
When brought in contact with an aqueous environment, such as body or tissue fluids which typically surround tissues or organs in an organism, the organic solvent dissipates or disperses into the aqueous or body fluid. Concurrently, the substantially insoluble thermoplastic base polymer precipitates or coagulates to form a flexible matrix or film which traps or encapsulates the biologically active agent. The polymeric controlled release additive reduces the initial burst of biologically active agent released from the polymeric composition as it coagulates to form a solid implant. Because the polymeric controlled release additive is also a thermoplastic polymer, it too, coagulates to form a part of the matrix. Once the solid implant is formed, the biologically active agent is released from the implant by diffusion or dissolution from within the polymeric matrix and/or the biologically active agent is released as the matrix is biodegraded, bioeroded or bioabsorbed.
Thermoplastic Polymers.
Thermoplastic polymers useful as base polymers in the polymeric composition include pharmaceutically acceptable polymers that are biodegradable, bioabsorbable, and/or bioerodible. The thermoplastic polymers are capable of substantially dissolving in a water-soluble carrier, or solvent, to form a solution. Examples of suitable biodegradable polymers include, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids) and copolymers, terpolymers and combinations thereof. Preferred thermoplastic polymers are polylactides, polyglycolides, polycaprolactones, polyanhydrides, and polyorthoesters.
The inherent viscosity (abbreviated as xe2x80x9cI.V.xe2x80x9d; units are in deciliters/gram) of the thermoplastic polymer is a measure of its molecular weight and degradation time (e.g., a thermoplastic polymer with a high inherent viscosity has a higher molecular weight and longer degradation time). Typically, a thermoplastic polymer with a high molecular weight provides a stronger matrix and the matrix takes more time to degrade. In contrast, a thermoplastic polymer with a low molecular weight degrades more quickly and provides a softer matrix. Preferably, the thermoplastic polymer has a molecular weight, as shown by the inherent viscosity, from about 0.10 dL/g to about 1.2 dL/g (as measured in chloroform), more preferably from about 0.10 dL/g to about 0.40 dL/g.
The molecular weight of the thermoplastic polymer can be varied by many methods known in the art. The choice of method is typically determined by the type of polymer. For example, the degree of polymerization can be controlled by varying the amount of initiator and/or reaction time.
Suitable thermoplastic polymers are soluble in an organic solvent. The solubility of a thermoplastic polymer in a solvent varies depending on the crystallinity, hydrophobicity, hydrogen-bonding and molecular weight of the polymer. Lower molecular weight polymers will normally dissolve more readily in an organic solvent than high-molecular weight polymers. A polymeric composition which includes a high molecular weight polymer tends to coagulate or solidify more quickly than a polymeric composition which includes a low-molecular weight polymer. Polymeric formulations which include high molecular weight polymers also tend to have a higher solution viscosity than a polymeric composition which includes a low-molecular weight polymer.
The viscosity of the flowable polymeric composition can vary from low viscosity, similar to that of water, to a high viscosity, similar to that of a paste, depending on the molecular weight and concentration of the thermoplastic polymer used in the composition. The viscosity can be varied such that the polymeric composition can be applied to a patient s tissues by any convenient technique, for example, by brushing, spraying, extruding. dripping, injecting, or painting. Different viscosities of the polymeric composition are preferable depending on the technique used to apply the composition. For example, spraying, via aerosolization, requires a polymeric composition having a low viscosity. In contrast, a polymeric composition with a higher viscosity may be desirable for other application techniques, for example, a polymeric composition having a putty-like consistency may be more preferable for bone regeneration applications. Typically, the polymeric composition includes about 10 wt % to about 80 wt %, more preferably about 30 wt % to about 60 wt % of a thermoplastic polymer.
Organic Solvents
Suitable organic solvents are those that are biocompatible, pharmaceutically acceptable, and miscible to dispersible in aqueous or body fluids. The organic solvent is capable of diffusing, dispersing, or leaching from the composition in situ into aqueous tissue or body fluid of the implant site, such as blood, serum, lymph, cerebral spinal fluid (CSF), or saliva.
Examples of suitable solvents include substituted heterocyclic compounds such as N-methyl-2-pyrrolidone (NMP), 2 pyrrolidone; esters of carbonic acid and alkyl alcohols such as propylene carbonate, ethylene carbonate and dimethyl carbonate; alkyl esters of mono-, di-, and tricarboxylic acids such as 2-ethyoxyethyl acetate, ethyl acetate, methyl acetate, ethyl lactate, ethyl butyrate, diethyl malonate, diethyl glutonate, tributyl citrate, diethyl succinate, tributyrin, isopropyl myristate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate, glyceryl triacetate; alkyl ketones such as acetone and methyl ethyl ketone; alcohols such as solketal, glycerol formal, and glycofurol; dialkylamides such as dimethylformamide, dimethylacetamide; dimethylsulfoxide (DMSO) and dimethylsulfone; tetrahydrofuran; lactones such as xcex5-caprolactone and butyrolactone; cyclic alkyl amides such as caprolactam; aromatic amides such as N,N-dimethyl-m-toluamide, and 1-dodecylazacycloheptan-2-one; and mixtures and combinations thereof. Preferred solvents include N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate, and propylene carbonate, solketal, glycerol formal, and glycofurol.
Typically, the polymeric composition includes about 20 wt % to about 90 wt %, more preferably about 40 wt % to about 70 wt % of an organic solvent.
Polymeric Controlled Release Additive
The polymeric composition of the invention also includes a polymeric controlled release additive. The presence of a polymeric controlled release additive in the polymeric composition substantially reduces the xe2x80x9cintitial burstxe2x80x9d of biologically active agent released from the polymeric composition during the initial 24 hours after implantation. As used herein, the term xe2x80x9csubstantially reducesxe2x80x9d means a decrease of at least 15% of biologically active agent released from the polymeric composition compared to a composition without the additive. Preferably, the polymeric controlled release additive reduces the initial burst of biologically active agent released from the polymeric composition by about 15% to about 70%, more preferably about 30% to about 60%, compared to a polymeric composition which does not include a controlled release additive.
According to the invention, the controlled release additive is a thermoplastic polymer having poly(lactide-co-glycolide) (PLG) moieties and polyethylene glycol (PEG) moieties. Preferably the controlled release additive is a PLG/PEG block copolymer which includes from about 50 mole % to about 90 mole % lactide monomers and about 50 mole % to about 10 mole % glycolide monomers. More preferably, the PLG/PEG block copolymer includes from about 50 mole % to about 75 mole % lactide monomers and about 50 mole % to about 25 mole % glycolide monomers. Preferably the PEG moiety has a molecular weight of about 1,000 Daltons to about 10,000 Daltons, more preferably about 5000 Daltons. The PEG portion of the block copolymer ranges from about 1 wt % to about 20 wt % of the total weight of the block copolymer. The percentage is dependent on the molecular weight of the block copolymer that is prepared and the molecular weight of the polyethylene glycol that is used. Thus, a block copolymer with a weight average molecular weight of 100,000 Daltons (I.V. approx. 0.8 dL/g) prepared with PEG having a molecular weight of 5,000 Daltons will contain about 5 wt % PEG. If PEG with a molecular weight of 1,000 Daltons is used, the block copolymer will include about 1 wt % of PEG.
The inherent viscosity (abbreviated as xe2x80x9cI.V.xe2x80x9d; units are in deciliters/gram) of the polymeric controlled release additive is a measure of its molecular weight. Preferably, the inherent viscosity of the controlled release additive is from about 0.50 dL/g to about 1.0 dL/g (as measured in chloroform), more preferably from about 0.70 dL/g to about 0.90 dL/g.
Suitable polymeric controlled release additives include any PLG/PEG block copolymer with the previously mentioned attributes. Examples of suitable polymeric controlled release additives include 50/50 PLG/PEG-5000 (0.81); 70/30 PLG/PEG-5000 (0.73); and 70/30 PLG/PEG-5000 (0.79).
The polymeric controlled release additive is present in the polymeric composition in an amount effective to reduce the initial burst of biologically active agent released from the polymeric composition during the first 24 hours after implantation. Preferably, the polymeric composition includes about 1 wt % to about 50 wt %, more preferably about 2 wt % to about 20 wt % of the polymeric controlled release additive.
Biologically-Active Agent.
The polymeric composition also includes a biologically-active agent. Biologically-active agents which may be used alone or in combination in the polymer system include medicaments, drugs, or other suitable biologically-, physiologically-, or pharmaceutically-active substances capable of providing a local or systemic biological, physiological or therapeutic effect and of being released from the resulting matrix into adjacent or surrounding tissue fluids. Upon implantation, the biologically active agent becomes incorporated into the implant matrix. The biologically active agent is capable of being released from the matrix into the adjacent tissue fluid and to the pertinent body tissue or organ, either adjacent to or distant from the implant site, preferably at a controlled rate. The release of the biologically active agent from the matrix may be varied, for example, by the solubility of the biologically active agent in an aqueous medium, the distribution of the agent within the matrix, the size, shape, porosity and solubility and biodegradability of the solid matrix.
The biologically-active agent may be soluble in the polymeric composition, to form a homogeneous mixture, or insoluble in the polymer formulation to form a suspension or dispersion. Preferably, the polymer formulation includes the biologically-active agent in an amount effective to provide the desired level of biological, physiological, pharmacological and/or therapeutic effect in the animal. The amount of biologically active agent incorporated into the polymeric formulation depends upon the desired release profile, the concentration of biologically active agent required for a biological effect, and the length of time that the drug should be released for treatment. There is generally no critical upper limit on the amount of the biologically active agent that can be included in the polymeric composition. However, the biologically active agent should not be present in such a high concentration that the biologically active agent significantly alters the viscosity of the polymeric composition and interferes with its application to a patient""s tissues. The lower limit of the amount of biologically active agent incorporated into the polymer formulation depends on the activity of the biologically active material and the period of time desired for treatment. Typically, the polymeric composition includes about 2 wt % to about 40 wt %, more preferably about 5 wt % to about 10 at % of a biologically active agent.
Examples of biologically active agents that are useful include substances capable of preventing an infection systemically in an animal or locally at the defect site, for example, anti-inflammatory agents such as hydrocortisone or prednisone; antibacterial agents such as penicillin, cephalosporins, bacitracin, tetracycline, doxycycline, gentamycin, quinolines, neomycin, clindamycin, kanamycin, or metronidazole; antiparasitic agents such as quinacrine, chloroquine, or vidarabine; antifungal agents such as nystatin; antiviral agents such as acyclovir, ribarivin, or interferons; analgesic agents such as salicylic acid, acetaminophen, ibuprofen, naproxen, piroxicam, flurbiprofen, or morphine; local anaesthetics such-as cocaine, lidocaine, bupivacaine, and benzocaine; immunogens (vaccines) for stimulating antibodies against hepititis, influenza, measles, rubella, tetanus, polio, and rabies; peptides such as leuprolide acetate (an LH-RH agonist), nafarelin, or ganirelix.
Substances which are capable of promoting growth and survival of cells and tissues or augmenting the functioning of cells, or metabolic precursors thereof are also useful biologically active agents, for example, a nerve growth promoting substance such as a ganglioside or a nerve growth factor; a hard or soft tissue growth promoting agent such as fibronectin (FN), human growth hormone (HGH), a colony stimulating factor, bone morphogenic protein, platelet-derived growth factor (PDGP), insulin-derived growth factor (IGF-I, IGF-II), transforming growth factor alpha (TGF-xcex1), transforming growth factor beta (TGF-xcex2), epidermal growth factor (EGF), fibroblast growth factor (FGF), or interleukin-1 (IL-1); an osteoinductive agent or bone growth promoting substance such as bone chips, or demineralized freeze-dried bone material; antineoplastic agents such as methotrexate, 5-fluorouracil, floxuridine, adriamycin, vinblastine, cisplatin, tumor-specific antibodies conjugated to toxins or tumor necrosis factor (TNF).
Other useful substances include hormones such as progesterone, testosterone, and follicle stimulating hormone (FSH) (birth control, fertility enhancement), insulin, or somatotrophins; antihistamines such as diphenhydramine, or chlorphencramine; cardiovascular agents such as digitalis, nitroglycerine, papaverine, or streptokinase; anti-ulcer agents such as cimetidine hydrochloride, or isopropamide iodide; bronchodilators such as metaprotenal sulfate, or aminophylline; vasodilators such as theophylline, niacin or minoxidil; central nervous system agents such as a tranquilizer, xcex2-adrenergic blocking agents, or dopamine; antipsychotic agents such as risperidone, olanzapine; narcotic antagonists such as naltrexone, naloxone or buprenorphine.
Polymeric Composition
The polymeric composition of the invention includes a base polymer, an organic solvent, a controlled release additive and a biologically active agent. According to the invention, the base polymer is a thermoplastic polymer that is soluble in the organic solvent and the organic solvent is miscible to dispersible in an aqueous medium, such as body or tissue fluids. Upon contact with an aqueous medium, the organic solvent diffuses or dissipates from the polymeric composition into the aqueous medium and the base polymer slowly precipitates or coagulates to form a solid matrix. The controlled release additive reduces the burst of biologically active agent released from the polymeric composition as it is coagulating to form the solid matrix or implant. The controlled release additive is preferably a PLG/PEG block copolymer.
The concentration of polymer (both the base polymer and the controlled release additive) in the polymeric composition may affect the rate at which the composition coagulates to form a matrix (e.g., a polymeric composition with a higher concentration of polymer may coagulate more quickly).
The percentage of polymer present in the composition may also affect the viscosity of the polymeric composition. For example, a composition having a higher percentage by weight of polymer is typically thicker and more viscous than a composition having a lower percentage by weight of polymer. A more viscous composition tends to flow more slowly. Therefore, a composition having a lower viscosity may be preferred in some instances, for example. when applying the formulation via an aerosol spray.
Formation of a Polymer Matrix
In general, a solid implant or matrix is formed by dispensing the flowable polymeric composition either into a tissue or onto the surface of a tissue which is surrounded by an aqueous medium. The composition can be applied to a patient""s tissues by any convenient technique, for example, by brushing, spraying, extruding, dripping, injecting, or painting.
Optionally, after the polymeric composition is applied to a tissue defect, an aqueous solution, such as a saline solution, can be applied over the polymeric composition to enhance coagulation of the thermoplastic polymer to form the matrix.
The Polymer Matrix
When the polymeric composition is applied to a tissue, the organic solvent slowly dissipates into the surrounding aqueous or body fluids and the substantially insoluble thermoplastic polymer precipitates or coagulates to form a polymer matrix. The polymeric controlled release additive reduces the initial burst of biologically active agent released from the polymeric composition as it coagulates to form a solid implant. Once the solid implant is formed, the biologically active agent is released from the implant by diffusion or dissolution from within the polymeric matrix and/or the biologically active agent is released as the matrix is biodegraded, bioeroded or bioabsorbed.
According to the invention, the resulting matrix is solid but is also able to conform with the irregular surface of the tissue.
The solid implant will slowly biodegrade within the body and will release the biologically active agent contained within its matrix at a controlled rate until depleted. With certain drugs, the polymer will degrade after the biologically active agent has been completely released. With other biologically active agents, such as peptides or proteins, the biologically active agent will be completely released only after the polymer has degraded to a point where the non-diffusing biologically active agent has been exposed to body or tissue fluids.
The solid matrix is capable of biodegradation, bioerosion and/or bioabsorption within the implant site of the animal. Generally, the implant matrix will breakdown over a period from about 1 week to about 12 months, preferably about 1 month to about 6 months.